Endothelin receptor antagonists

ABSTRACT

Novel pyrroles, pyrazoles and triazoles, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists are described.

This is a divisional of application Ser. No. 09/121,545 filed Jul. 23,1998, which is a continuation of prior application Ser. No. 08/718,562,filed Feb. 2, 1998 now abandoned; which is a 371 of InternationalApplication No. PCT/US96/12581, filed Aug. 2, 1996; which claims thebenefit of priority from the following provisional applications:60/001,792, filed Aug. 2, 1995 and 60/010,982, filed Feb. 1, 1996.

FIELD OF INVENTION

The present invention relates to novel pyrroles, pyrazoles andtriazoles, pharmaceutical compositions containing these compounds andtheir use as endothelin receptor antagonists.

Endothelin (ET) is a highly potent vasoconstrictor peptide synthesizedand released by the vascular endothelium. Endothelin exists as threeisoforms, ET-1, ET-2 and ET-3. Unless otherwise stated "endothelin"shall mean any or all of the isoforms of endothelin!. Endothelin hasprofound effects on the cardiovascular system, and in particular, thecoronary, renal and cerebral circulation. Elevated or abnormal releaseof endothelin is associated with smooth muscle contraction which isinvolved in the pathogenesis of cardiovascular, cerebrovascular,respiratory and renal pathophysiology. Elevated levels of endothelinhave been reported in plasma from patients with essential hypertension,acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis,and patients with uraemia undergoing dialysis.

In vivo, endothelin has pronounced effects on blood pressure and cardiacoutput. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in ratscauses a transient, dose-related depressor response (lasting 0.5 to 2minutes) followed by a sustained, dose-dependent rise in arterial bloodpressure which can remain elevated for 2 to 3 hours following dosing.Doses above 3 nmol/kg in a rat often prove fatal.

Endothelin appears to produce a preferential effect in the renalvascular bed. It produces a marked, long-lasting decrease in renal bloodflow, accompanied by a significant decrease in GFR, urine volume,urinary sodium and potassium excretion. Endothelin produces a sustainedantinatriuretic effect, despite significant elevations in atrialnatriuretic peptide. Endothelin also stimulates plasma renin activity.These findings suggest that ET is involved in the regulation of renalfunction and is involved in a variety of renal disorders including acuterenal failure, cyclosporine nephrotoxicity, radio contrast induced renalfailure and chronic renal failure.

Studies have shown that in vivo, the cerebral vasculature is highlysensitive to both the vasodilator and vasoconstrictor effects ofendothelin. Therefore, ET may be an important mediator of cerebralvasospasm, a frequent and often fatal consequence of subarachnoidhemorrhage.

ET also exhibits direct central nervous system effects such as severeapnea and ischemic lesions which suggests that ET may contribute to thedevelopment of cerebral infarcts and neuronal death.

ET has also been implicated in myocardial ischemia (Nichols et al. Br.J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Circ. Res., 65:1193-1200, 1989) coronary vasospasm (Fukuda et al., Eur. J. Pharm. 165:301-304, 1989 and Luscher, Circ. 83: 701, 1991) heart failure,proliferation of vascular smooth muscle cells, (Takagi, Biochem &Biophys. Res. Commun.; 168: 537-543, 1990, Bobek et al., Am. J. Physiol.258:408-C415, 1990) and atherosclerosis, (Nakaki et al., Biochem. &Biophys. Res. Commun. 158: 880-881, 1989, and Lerman et al., New Eng. J.of Med. 325: 997-1001, 1991). Increased levels of endothelin have beenshown after coronary balloon angioplasty (Kadel et al., No. 2491 Circ.82: 627, 1990).

Further, endothelin has been found to be a potent constrictor ofisolated mammalian airway tissue including human bronchus (Uchida etal., Eur J. of Pharm. 154: 227-228 1988, LaGente, Clin. Exp. Allergy 20:343-348, 1990; and Springall et al Lancet, 337: 697-701, 1991).Endothelin may play a role in the pathogenesis of interstitial pulmonaryfibrosis and associated pulmonary hypertension. Glard et al., ThirdInternational Conference on Endothelin, 1993, p. 34 and ARDS (AdultRespiratory Distress Syndrome), Sanai et al., Supra, p. 112.

Endothelin has been associated with the induction of hemorrhagic andnecrotic damage in the gastric mucosa (Whittle et al., Br. J. Pharm. 95:1011-1013, 1988); Raynaud's phenomenon, Cinniniello et al., Lancet 337:114-115, 1991); Crohn's Disease and ulcerative colitis, Munch et al.,Lancet, Vol. 339, p. 381; Migraine (Edmeads, Headache, February 1991 p127); Sepsis (Weitzberg et al., Circ. Shock 33: 222-227, 1991; Pittet etal., Ann. Surg. 213: 262-264, 1991), Cyclosporin-induced renal failureor hypertension (Eur, J. Pharmacol., 180: 191-192, 1990, Kidney Int. 37:1487-1491, 1990) and endotoxin shock and other endotoxin induceddiseases (Biochem. Biophys. Res. Commun., 161: 1220-1227, 1989, ActaPhysiol. Scand. 137: 317-318, 1989) and inflammatory skin diseases.(Clin Res. 41:451 and 484, 1993).

Endothelin has also been implicated in preclampsia of pregnancy. Clarket al., Am. J. Obstet. Gynecol. March 1992, p. 962-968; Kamor et al., N.Eng. J. of Med., Nov. 22, 1990, p. 1486-1487; Dekker et al., Eur J. Ob.and Gyn. and Rep. Bio. 40 (1991) 215-220: Schiff et al., Am. J. Ostet.Gynecol. February 1992, p. 624-628; diabetes mellitus. Takahashi et al.,Diabetologia (1990) 33:306-310; and acute vascular rejection followingkidney transplant, Watschinger et al., Transplantaton Vol. 52, No. 4,pp. 743-746.

Endothelin stimulates both bone resorption and anabolism and may have arole in the coupling of bone remodeling. Tatrai et al. Endocrinology,Vol. 131, p. 603-607.

Endothelin has been reported to stimulate the transport of sperm in theuterine cavity, Casey et al., J. Clin. Endo and Metabolism, Vol. 74, No.1, p. 223-225, therefore endothelin antagonists may be useful as malecontraceptives. Endothelin modulates the ovarian/menstrual cycle,Kenegsberg, J. of Clin. Endo. and Met., Vol. 74, No. 1, p. 12, and mayalso play a role in the regulation of penile vascular tone in man, Lauet al., Asia Pacific J. of Pharm., 1991, 6:287-292 and Tejada et al., J.Amer. Physio. Soc. 1991, H1078-H1085. Endothelin also mediates a potentcontraction of human prostatic smooth muscle, Langenstroer et al., J.Urology, Vol. 149, p. 495-499.

Thus, endothelin receptor antagonists would offer a unique approachtoward the pharmacotherapy of hypertension, acute and chronic renalfailure, ischemia induced renal failure, sepsis-endotoxin induced renalfailure, prophylaxis and/or treatment of radio-contrast induced renalfailure, acute and chronic cyclosporin induced renal failure,cerebrovascular disease, cerebrovascular spasm, subarachnoid hemorrhage,myocardial ischemia, angina, congestive heart failure, acute coronarysyndrome, myocardial salvage, unstable angina, asthma, primary pulmonaryhypertension, pulmonary hypertension secondary to intrinsic pulmonarydisease, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis,migraine, glaucoma, endotoxin shock, endotoxin induced multiple organfailure or disseminated intravascular coagulation, cyclosporin-inducedrenal failure and as an adjunct in angioplasty for prevention ofrestenosis, diabetes, diabetic retinopathy, retinopathy, diabeticnephropathy, diabetic macrovascular disease, atherosclerosis,preclampsia of pregnancy, bone remodeling, kidney transplant, malecontraceptives, infertility and priaprism and benign prostatichypertrophy.

SUMMARY OF THE INVENTION

This invention comprises compounds represented by Formula (I) andpharmaceutical compositions containing these compounds, and their use asendothelin receptor antagonists which are useful in the prevention ortreatment of a variety of cardiovascular and renal diseases includingbut not limited to: hypertension, acute and chronic renal failure,cyclosporine induced nephrotoxicity, benign prostatic hypertrophy,pulmonary hypertension, migraine, stroke, subarachnoid hemorrhage,cerebrovascular vasospasm, myocardial ischemia, angina, congestive heartfailure, unstable angina, coronary vasospasm and myocardial salvage, thesequelae of diabetes including but not limited to: atherosclerosis,diabetic nephropathy, diabetic retinopathy, retinopathy, diabeticmacrovascular disease; and as an adjunct in angioplasty for preventionof restenosis.

This invention further constitutes a method for antagonizing endothelinreceptors in an animal, including humans, which comprises administeringto an animal in need thereof an effective amount of a compound ofFormula (I).

This invention also constitutes intermediates represented by Formula(II). In a further aspect, the present invention provides a process forthe preparation of a compound of Formula (I)(d).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by structural Formula(I): ##STR1## wherein (Z) is ##STR2## P is tetrazol-5-yl. CO₂ R₆ orC(O)N(R₆)S(O)_(q) R₁₀ ;

R^(a) is independently hydrogen or C₁₋₆ alkyl;

R₁ is independently hydrogen, Ar, C₁₋₆ alkyl or C₁₋₆ alkoxy;

R₂ is ##STR3## R₃ and R₅ are independently R₁₃ OH, C₁₋₈ alkoxy, S(O)_(q)R₁₁, N(R₆)₂, NO₂, Br, F, I, Cl, CF₃, NHCOR₆, R₁₃ CO₂ R₇, --X--Rg--Y,--X(C(R₆)₂)OR₆, --(CH₂)_(m) X'R₈ or --X(CH₂)_(n) R₈ wherein eachmethylene group within --X(CH₂)_(n) R₈ may be unsubstituted orsubstituted by one or two --(CH₂)_(n) Ar groups;

R₄ is independently R₁₁, OH, C₁₋₅ alkoxy, S(O)_(q) R₁₁, N(R₆)₂, Br, F,I, Cl or NHCOR₆, wherein the C₁₋₅ alkoxy may be unsubstituted orsubstituted by OH, methoxy or halogen;

R₆ is independently hydrogen or C₁₋₈ alkyl;

R₇ is independently hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈alkynyl, all of which may be unsubstituted or substituted by one or moreOH, N(R₆)₂, CO₂ R₁₂, halogen or XC₁₋₁₀ alkyl; or R₇ is (CH₂)_(n) Ar;

R₈ is independently R₁₁, CO₂ R₇, CO₂ C(R₁₁)₂ O(CO)XR₇, PO₃ (R₇)₂, SO₂NR₇ R₁₁, NR₇ SO₂ R₁₁, CONR₇ SO₂ R₁₁, SO₃ R₇, SO₂ R₇, P(O)(OR₇)R₇, CN,CO₂ (CH₂)_(m) C(O)N(R₆)₂, C(R₁₁)₂ N(R₇)₂, C(O)N(R₆)₂, NR₇ C(O)NR₇ SO₂R₁₁, OR₆, or tetrazole which is substituted or unsubstituted by C₁₋₆alkyl;

R₉ is independently a bond, C₁₋₁₀ alkylene, C₁₋₁₀ alkenylene, C₁₋₁₀akylidene, C₁₋₁₀ alkynylene, all of which may be linear or branched, orphenylene, all of which may be unsubstituted or substituted by one ofmore OH, N(R₆)₂, COOH or halogen;

R₁₀ is independently C₁₋₁₀ alkyl, N(R₆)₂ or Ar;

R₁₁ is independently hydrogen, Ar, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, all of which may be substituted or unsubstituted by one or moreOH, CH₂ OH, N(R₆)₂, or halogen;

R₁₂ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₇ alkynyl;

R₁₃ is independently divalent Ar, C₁₋₁₀ alkylene, C₁₋₁₀ alkylidene,C₂₋₁₀ alkenylene, all of which may be unsubstituted or substituted byone or more OH, CH₂ OH, N(R₆)₂ or halogen;

R₁₄ is independently hydrogen, C₁₋₁₀ alkyl, XC₁₋₁₀ alkyl, Ar or XAr;

R₁₅ is independently hydrogen, Ar, C₁₋₆ alkyl, or XAr;

R₁₆ is independently C₁₋₆ alkyl or phenyl substituted by one or moreC₁₋₆ alkyl, OH, C₁₋₅ alkoxy, S(O)_(q) R₆, N(R₆)₂, Br, F, I, Cl, CF₃ orNHCOR₆ ;

X is independently (CH₂)_(n), O, NR₆ or S(O)_(q) ;

X' is independently O, NR₆ or S(O)_(q) ;

Y is independently CH₃ or X(CH₂)_(n) Ar;

Ar is: ##STR4## naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl,thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl,imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl,morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimnidyl; all ofwhich may be unsubstituted or substituted by one or more Z₁ or Z₂groups;

A is independently C═0, or (C(R₆)₂)_(m) ;

B is independently --CH₂ -- or --0--;

Z₁ and Z₂ are independently hydrogen, XR₆, C₁₋₈ alkyl, (CH₂)_(q) CO₂ R₆,C(O)N(R₆)₂, CN, (CH₂)_(n) OH, NO₂, F, Cl, Br, I, N(R₆)₂, NHC(O)R₆,O(CH₂)_(m) C(O)NR_(a) SO₂ R₁₆, (CH₂)_(m) OC(O)NR_(a) SO₂ R₁₆, O(CH₂)_(m)NR_(a) C(O)NR_(a) SO₂ R₁₆ tetrazolyl which may be substituted orunsubstituted by C₁₋₆ alkyl, CF₃ or C(O)R₆ ;

m is independently 1 to 3;

n is independently 0 to 6;

q is independently 0, 1 or 2;

provided R₃, R₄ and R₅ are not O--O(CH₂)_(n) Ar or O-OR₆ ;

or a pharmaceutically acceptable salt thereof.

All alkyl, alkenyl, alkynyl and alkoxy groups may be straight orbranched.

Halogen may be Br, Cl, F or I.

The compounds of the present invention may contain one or moreasymmnetric carbon atoms and may exist in racemic and optically activeform. All of these compounds and their diastereoisomers are contemplatedto be within the scope of the present invention.

Preferred compounds are those wherein:

P is CO₂ R₆ ; more preferably P is CO₂ H.

R₁ is hydrogen.

Z₁ and Z₂ are independently hydrogen, CO₂ R₆, (CH₂)_(n) OH, C₁₋₄ alkylor

C₁₋₆ alkoxy, e.g. methoxy.

R₃ and R₅ are independently hydrogen, CO₂ R₆, OH, C₁₋₈ alkoxy,

C₁₋₈ alkyl, N(R₆)₂, NO₂, Br, F, Cl, I, R₁₃ CO₂ R₇, X(CH₂)_(n) R₈,(CH₂)mX'R₈, or

X(C(R₆)₂)_(m) OR₆.

In the context of the group R₃ and R₅ preferably do not representhydrogen. In particular in the group R₃ preferably represents Br, Cl,C₁₋₉ alkoxy e.g. methoxy;

X(CH₂)_(n) R₈, wherein X preferably represents O, n is 0, 1, or 2, andR₈ is preferably selected from:

CO₂ R₆ wherein R₆ is preferably hydrogen;

OR₆ wherein R₆ is preferably H;

tetrazolyl optionally substituted by C₁₋₈ alkyl e.g. ethyl;

CONR₇ SO₂ R₁₁ wherein R₇ is H or C₁₋₈ alkyl e.g. methyl, R₁₁ preferablyis C₁₋₈ alkyl (e.g. methyl, isopropyl, or t-butyl) or phenyl optionallysubstituted by Br, Cl, F, C₁₋₈ alkyl e.g. methyl;

or R₈ is phenyl or pyridyl substituted by one or more Br, Cl, CO₂ H, CH₂OH; and

R₅ is C₁₋₈ alkoxy e.g. methoxy, or N(R₆)₂ wherein R₆ preferably is H ormethyl.

R₄ is hydrogen, OH, C₁₋₅ alkoxy, N(R₆)₂, Br, F, Cl, I, NHCOCH₃, orS(O)_(q) C₁₋₅ alkyl wherein the C₁₋₅ alkyl may be unsubstituted orsubstituted by OH methoxy or halogen. R₄ is more preferably hydrogen.

R₆ is hydrogen or C₁₋₈ alkyl e.g. methyl and ethyl.

R₇ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl, all of whichmay be unsubstituted or substituted by one or more OH, N(R₆)₂, CO₂ R₁₂,halogen, or R₇ is (CH₂)_(n) Ar. When R₇ is (CH₂)_(n) Ar, n is preferablyzero or 1 and Ar is preferably phenyl substituted or unsubstitued byhalogen or C₁₋₅ alkoxy.

R₁₁ is hydrogen, phenyl, pyridyl wherein the phenyl and pyridyl may besubstituted or unsubstituted by one or two C₁₋₄ alkyl groups; C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, all of which may be substituted orunsubstituted by one or more OH, CH₂ OH, N(R₆)₂, or halogen;

R₁₂ is hydrogen or C₁₋₆ alkyl.

R₁₃ is phenyl, pyridyl, or C₂₋₁₀ alkylene, all of which may beunsubstituted or substituted by one or more CO₂ R₆, OH, CH₂ OH, N(R₆)₂,or halogen;

R₁₅ is preferably hydrogen or C₁₋₆ alkyl e.g. ethyl, isopropyl, n-butyl,cyclopropylmethyl or cyclopropylethyl.

(Z) is preferably (d).

Preferred compounds are:

(E)-3- 1-n-Butyl-5-2-(2-carboxy-6-chlorophenyl)methoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid;

(E)-3- 1-n-Butyl-5-2-(2-carboxyphenyl)methoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid;

(E)-3- 1-n-Butyl-5-2-(2-carboxyphenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid;

(E)-3- 1-n-Butyl-5-2-(2-carboxy-6-chlorophenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid;

(E)-3- 1-n-Butyl-5-2-(2-carboxy-5-chlorophenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid;

(E)-3- 1-n-Butyl-5-2-(3-carboxy-2-pyridyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-5-yl)methyl!-prop-2-enoic acid; or

(E)-3- 1-n-Butyl-5-2-(2-carboxy-5-chlorophenyl)methoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid.

The present invention provides compounds of Formula (I), which may bemade by methods similar to those given below.

Compounds of the Formula (Id): ##STR5## wherein one B is CH₂ and theother is O can be prepared by alkylating a ketone of Formula (2):##STR6## in dimethyl carbonate in the presence of sodium hydride toprovide a b-keto ester of Formula (3). ##STR7## Condensation of a b-ketoester of Formula (3) with dimethyl formate dimethyl acetal in a suitablesolvent such as toluene at approximately 95° C. affords a compound ofFormula (4). ##STR8##

Treatment of a compound of Formula (4) with a hydrazine derivative ofthe Formula (5)

    R.sub.15 --NH--NH.sub.2                                    ( 5)

wherein R₁₅ is C₁₋₆ alkyl;

in suitable solvents such as methanol and water in the presence ofsodium acetate provides a pyrazole of Formula (6). ##STR9##

Reduction of an ester of Formula (6) with a reducing agent such asdiisobutylalluminum hydride in a solvent such as dichloromethanefollowed by oxidation with an oxidant such as Jones reagent in acetoneaffords an aldehyde of Formula (7). ##STR10##

Knoevenagel condensation of an aldehyde of Formula (7) with a half acidof Formula (8), wherein R₁₆ is C₁₋₈ alkyl ##STR11## in a solvent such asbenzene at reflux, in the presence of piperidinium acetate withazeotropic removal of water using a Dean-Stark apparatus to afford anester of Formula (9). ##STR12##

Followed if necessary and desired by:

1) deprotection and alkylation and hydrolysis of the R₃, R₄, R₅, R₁₅,R₁₆, Z₁ and Z₂ groups as required and;

2) salt formation

Aldehyde condensation may be effected by heating in the presence ofpyridine and acetic acid.

Conversion of an ester of formula (9) into an acid may be carried outusing conventional deprotection techniques i.e. hydrolysis.

A half acid of Formula (8), ##STR13## wherein R₁₆ is C₁₋₈ alkyl and n is1, may be prepared starting from 4-methoxyphenol (10) ##STR14## whichupon bromination affords a bromobenzene of Formula (11). ##STR15##

Alkylation of phenol of Formula (11) with 1,2-dichloroethane under phasetransfer reaction conditions provides a compound of Formula (12).##STR16##

Treatment of bromobenzene of Formula (12) with an organolithium reagentsuch n-buryllithium or metal such as magnesium in a solvent such astetrahydrofuran affords dihydrobenzofuran of Formula (13). ##STR17##

Bromination of a compound of Formula (13) with hexamethylenetetraaminehydrobromide perbromide in a solvent such as dichloromethane providesbromodihydrobenzofuran of Formula (14). ##STR18##

Metal-halogen exchange of compound of Formula (14) using anorganolithium reagent such n-butyllithium in a solvent such astetrahydrofuran affords an aldehyde of Formula (15). ##STR19##

Condensation of an aldehyde of Formula (15) with dialkyl malonate suchas diethyl malonate in the presence of piperidine and acetic acid in asolvent such as benzene provides an a,b-unsatuated ester of Formula(16). ##STR20##

Treatment of an a,b-unsatuated ester of Formula (16) with sodiumborohydride in ethanol followed by mono saponification with aqueoussodium hydroxide in a solvent such as ethanol affords, afteracidification with aqueous hydrochloric acid, an acid of Formula (8),whereas R₁₆ is ethyl and n is 1.

Other compounds of Formula (Id) may be made by methods well known in theart. The invention also is a process for preparing compounds of Formula(Id)by:

(a) reaction of a compound of Formula (II) ##STR21## or a protected formor precursor thereof (as defined hereinafter) with a compound of Formula(8) ##STR22## wherein one B is CH₂ and the other is O, and Z₁, Z₂ andR₁₆ are as defined for Formula (Id) hereinabove;

followed if necessary or desired by:

(b) conversion of one compound of Formula (Id) into a different compoundof Formula (Id) e.g.

(i) when Formula (Id) contains a group CO₂ R₆, CO₂ R₇ or CO₂ R₁₂, or CO₂R₁₆ wherein R₆, R₇, R₁₂ or R₁₆ is alkyl, conversion to a correspondingcompound where R₆, R₇, R₁₂ or R₁₆ represents hydrogen;

(ii) when Formula (Id) contains hydroxy group (e.g. in R₃, R₄ or R₅)conversion to a different group, e.g. a group (CH₂)Ar where Ar isoptionally substituted phenyl, by method well known in the art; and/or

(c) salt formation.

It will be appreciated by those skilled in the art that the substituentsR₁₅, R₃, R₄ and R₅ and be introduced at any appropriate stage of thesynthesis, preferably at an early stage, using methods well known in theart. In some of the reactions depicted above, particularly those in theearly stages of the overall synthesis, one or more of the substitutentsR₁₅, R₃, R₄ and R₅ may therefore represent a precursor for the eventualsubstituent. A precursor for any of the substitutents R₁₅, R₃, R₄ and R₅means a group which may be derivatised or converted into the desiredgroup R₁₅, R₃, R₄ and R₅. It will be further appreciated that it may benecessary or desirable to protect certain of these substitutents (ortheir precursors) at various stages in the reaction sequence. Suitableprecursors and protecting groups as well known to those skilled in theart, as are methods for their conversion of removal respectively.

In another aspect the invention provides for an intermediate of theformula (II) wherein R₁₅, R₃, R₄, R₅ and R^(a) are as described forFormula (I)

Compounds of Formula (Ii) ##STR23## wherein one B is CH₂ and the otheris O; can be prepared starting by commercially available ketones ofFormula (17) ##STR24## by reaction with diethyl oxalate of Formula (18)##STR25## in the presence of a base such as sodium ethoxide in a solventsuch as ethanol to produce a diketone of Formula (19). ##STR26##Reaction of a diketone of Formula (19) with hydrazine derivative ofFormula (20) ##STR27## in a suitable solvent such as ethanol at refluxprovides a pyrazole of Formula (21). ##STR28##

Saponification of an ester of Formula (21) using lithium hydroxide in asolvent such as aqueous methanol affords, after acidification an acid ofthe Formula (22), ##STR29## which can be subsequently converted to thecorresponding N-methoxy-N-methylamide of Formula (23) ##STR30## bytreatment with methyl chloroformate followed byN,O-dimethylhydroxylamine hydrochloride in the presence of a base suchas N-methylpiperidine. Compound of Formula (23) can be treated with anorganometallic reagent R^(a) -M wherein R^(a) is C₁₋₆ alkyl and M is Lior MgCl; to provide a compound of Formula (24), wherein R^(a) is C₁₋₆alkyl. ##STR31##

Alternatively, reaction of compound (24), wherein R^(a) is C₁₋₆ alkyl,with Lawesson's reagent in a suitable solvent such as tetrahydrofuranaffords a thione of Formula (25), ##STR32## which can be treated withthe diazoester (26) ##STR33## in refluxing tetrahydrofuran to provide athiirane of Formula (27). ##STR34##

Treatment of a thiirane of Formula (27) with trimethylphosphite atreflux in a solvent such as chloroform provides compounds of Formula(28), wherein R^(a) is C₁₋₆ alkyl. ##STR35##

Saponification of an ester of Formula (28) using lithium hydroxide in asolvent such as aqueous methanol affords, after acidification withacetic acid, an acid of the Formula (Ii), wherein P is CO₂ H. Compoundsof the Formula (Ie) ##STR36## wherein one B is CH₂ and the other is O;can be prepared following the steps outlined in the following Scheme##STR37## starting from an aryl ester of Formula (29), wherein R₁₆ isC₁₋₈ alkyl, to provide a pyrrole of Formula (30). Compound of Formula(30) can be subsequently converted to compounds of Formula (Ie)following the same sequence of steps as the one described above for theconversions of compound (6) and compound (21) to compounds (Id) andcompound (Ii), respectively.

Compounds of Formula (Ih) may be prepared starting from a boronic acidof Formula (31) ##STR38## with a triazole of Formula (32), wherein X isCr or Br; ##STR39## under standard Suzuki coupling conditions to providean ester of Formula (33) ##STR40##

A compound of Formula (31) may be prepared by reaction of acorresponding organometallic derivative (eg lithium or Grignard) with atrialkyl borate followed by hydrolysis.

A compound of Formula (32) may be prepared starting from dimethylmalonate with p-acetaminobenzenesulfonyl azide in a solvent such asacetonitrile in the presence of a base such as triethyl amine to providedimethyl diazomalonate (34). ##STR41##

Treatment of diazomalonate of Formula (34) with an amine of Formula (35)

    R.sub.15 --NH.sub.2                                        ( 35)

followed by acidic work up provides a triazole of Formula (36) ##STR42##

Reaction of a compound of Formula (36) with PX₅, whereas X is Br or Cl,in the presence of potassium carbonate in dimethylformamide affords acompound of Formula (32).

Compounds of Formula (Ij) may be prepared starting from an analine ofFormula (37) ##STR43## with a diketone of Formula of (38) ##STR44## in asuitable solvent such as ethyl alcohol at reflux to provide a pyrrole ofFormula (39). ##STR45##

A diketone of Formula of (38) can be prepared by reacting ofa,b-unsatuated ketone of Formula (40) ##STR46## with a silyl enol etherof Formula (41) ##STR47## in the presence of Lewis acid such as zincchloride in a suitable solvent such as dichloromethane followed byacidic hydrolysis. Compounds of Formula (33) and compounds of Formula(39) can be subsequently converted to compounds of Formula (Ih) andcompounds of Formula (Ij), respectively, following the same sequence ofsteps as the one described above for the conversions of compound (6),compound (21) and compound (30) to compounds (Id), compound (Ii) andcompound (Ie), respectively.

In order to use a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals itis normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

Compounds of Formula (I) and their pharmaceutically acceptable salts maybe administered in a standard manner for the treatment of the indicateddiseases, for example orally, parenterally, sub-lingually,transdermally, rectally, via inhalation or via buccal administration.

Compounds of Formula (I) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as syrups, tablets,capsules and lozenges. A syrup formulation will generally consist of asuspension or solution of the compound or salt in a liquid carrier forexample, ethanol, peanut oil, olive oil, glycerine or water with aflavoring or coloring agent. Where the composition is in the form of atablet, any pharmaceutical carrier routinely used for preparing solidformulations may be used. Examples of such carriers include magnesiumstearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid,starch, lactose and sucrose. Where the composition is in the form of acapsule, any routine encapsulation is suitable, for example using theaforementioned carriers in a hard gelatin capsule shell. Where thecomposition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example aqueous gums, celluloses,silicates or oils and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous or non-aqueous carrieroptionally containing a parenterally acceptable oil, for examplepolyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, orsesame oil.

Typical compositions for inhalation are in the form of a solution,suspension or emulsion that may be administered as a dry powder or inthe form of an aerosol using a conventional propellant such asdichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (1) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats or their synthetic analogues.

Typical transdermal formulations comprise a conventional aqueous ornon-aqueous vehicle, for example a cream, ointment, lotion or paste orare in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer tothemselves a single dose.

Each dosage unit for oral administration contains suitably from 0.1 mgto 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosageunit for parenteral administration contains suitably from 0.1 mg to 100mg, of a compound of Formula (I) or a pharmaceutically acceptable saltthereof calculated as the free acid. Each dosage unit for intranasaladministration contains suitably 1-400 mg and preferably 10 to 200 mgper person. A topical formulation contains suitably 0.01 to 1.0% of acompound of Formula (I).

The daily dosage regimen for oral administration is suitably about 0.01mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for parenteral administration is suitably about 0.001 mg/Kg to40 mg/Kg, of a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. The daily dosageregimen for intranasal administration and oral inhalation is suitablyabout 10 to about 500 mg/person. The active ingredient may beadministered from 1 to 6 times a day, sufficient to exhibit the desiredactivity.

No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the present invention.

The biological activity of the compounds of Formula (I) are demonstratedby the following tests:

I. Binding Assay

A) CHO cell membrane preparation.

CHO cells stably transfected with human ET_(A) and ET_(B) receptors weregrown in 245 mm×245 mm tissue culture plates in Dulbecco's modifiedEagle's medium supplemented with 10% fetal bovine serum. The confluentcells were washed with Dulbecco's phosphate-buffered saline containing aprotease inhibitor cocktail (5 mM EDTA, 0.5 mM PMSF, 5 ug/ml ofleupeptin and 0.1 U/ml of aprotinin) and scraped in the same buffer.After centrifugation at 800×g, the cells were lysed by freezing inliquid nitrogen and thawing on ice followed by homogenization (30 timesusing a glass dounce homogenizer) in lysis buffer containing 20 mM TrisHCI, pH 7.5, and the protease inhibitor cocktail. After an initialcentrifugation at 800×g for 10 min to remove unbroken cells and nuclei,the supernatants were centrifuged at 40,000×g for 15 min and the pelletwas resuspended in 50 mM Tris HCI, pH 7.5, and 10 mM MgCl₂ and stored insmall aliquots at -70° C. after freezing in liquid N₂. Protein wasdetermined by using the BCA method and BSA as the standard.

(B) Binding studies.

¹²⁵ I!ET-1 binding to membranes prepared from CHO cells was performedfollowing the procedure of Elshourbagy et al. (1993). Briefly, the assaywas initiated in a 100 ul volume by adding 25 ul of ¹²⁵ I!ET-1 (0.2-0.3nM) in 0.05% BSA to membranes in the absence (total binding) or presence(nonspecific binding) of 100 nM unlabeled ET-1. The concentrations ofmembrane proteins were 0.5 and 0.05 ug per assay tube for ET_(A) andET_(B) receptors, respectively. The incubations (30° C. 60 min) werestopped by dilution with cold buffer (20 mM Tris HCI. pH 7.6, and 10 mMMgCl₂) and filtering through Whatman GF/C filters (Clifton, N.J.)presoaked in 0.1% BSA. The filters were washed 3 times (5 ml each time)with the same buffer by using a Brandel cell harvester and were countedby using a gamma counter at 75% efficiency.

The following examples are illustrative and are not limiting of thecompounds of this invention.

EXAMPLE 1 (E)-3- 1-n-Butyl-5-2-(2-carboxy-6-chlorophenyl)methoxy-4-chlorophenyl!-1H-pyrazola-4-yl!-2-(5-methoxy-2,3-diydrobenzofuran-6-yl)methyl!-prop-2-enoic acid

a) 2-Bromo-4-methoxyphenol

To a solution of 4-methoxyphenol (13.00 g, 104.84 mmol) in DMF (50 mL)was added bromine (5.40 mL, 104.84 mmol) at 0° C. The reaction wasallowed to warm to room temperature. After stirring for 2 h the reactionwas quenched with water and extracted with ethyl acetate (3×200 mL). Thecombined organic extracts were washed with brine and dried (Na₂ SO₄).Removal of the solvent under reduced pressure gave 21.28 g of the crudetitle compound as a dark oil: ¹ H NMR (250 MHz, CDCl₃) d 7.49 (b, 1H),6.96 (d, 1H), 6.72-6.62 (m, 2H), 3.71 (s, 3H).

b) 2-Bromo-1-(2-chloroethoxy)-4-methoxybenzene

To a solution of 2-bromo-methoxyphenol (20.00 g, 98.04 mmol) in1,2-dichloroethane (50.00 mL, 0.63 mol) was added sodium hydroxide(12.00 g, 0.29 mol) and benzyltriethylammonium chloride (3.00 g) inwater (150 mL). The mixture was stirred at reflux for 24 h and extractedwith ethyl acetate (3×150 mL). The combined organic extracts were washedwith brine and dried (Na₂ SO₄). After removing the solvent under reducedpressure, flash chromatography (1:1 diethyl ether/hexane) of the residuegave 14.20 g (66% over two steps) of the title compound as a yellow oil:¹ H NMR (250 MHz, CDCl₃) d 7.09 (d, 1H), 6.82-6.72 (m, 2H), 4.27 (t,2H), 3.75 (t, 3H), 3.71 (s, 3H).

c) 5-Methoxy-2,3-dihydrobenzofuran

To a solution of 2-bromo-1-(2-chloroethoxy)-4-methoxybenzene (1.38 g,5.22 mmol) in THF was added 190 mg (7.82 mmol) of Mg and MeI (3 mL). Themixture was sonicated for 2 h and stirred at room temperature foradditional 20 h. The reaction was quenched with 3N HCl (50 mL) andextracted with 1:1 hexane/ethyl acetate (3×50 mL). The combined organicextracts were washed with saturated NaHCO₃ brine and dried (Na₂ SO₄).After removing the solvent under reduced pressure, flash chromatography(3:1 hexane/ethyl acetate) of the residue gave 0.66 g (85%) of the titlecompound as a colorless liquid: ¹ H NMR (400 MHz, CDCl₃) d 6.80 (d, 1H),6.70 (d, 1H), 6.65 (dd, 1H), 4.53 (t, 2H), 3.75 (s, 3H), 3.18 (t, 3H).

d) 6-Bromo-5-methoxy-2,3-dihydrobenzofuran

To a solution of 5-methoxy-2,3-dihydrobenzofuran (1.00 g, 6.66 mmol) indichloromethane (10 mL) was added hexamethylenetetraamine hydrobromideperbromide (2.79g, 7.32 mmol) at -78° C. The reaction was allowed towarm to room temperature. After stirring for 3 h, the reaction wasquenched with water and extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were washed with brine and dried (Na₂ SO₄).Removal of the solvent under reduced pressure gave 1.45 g (96%) of thetitle compound as a dark solid: ¹ H NMR (250 MHz, CDCl₃) d 7.00 (s, 1H),6.82 (s, 1H), 4.57 (t, 2H), 3.81 (s, 3H), 3.15 (t, 2H).

e) 5-Methoxy-2,3-dihydrobenzofuran-6-al

To a solution of 6-bromo-5-methoxy-2,3-dihydrobenzofuran (9.20 g, 40.35mmol) in THF (50 mL) was dropwise added n-Butyl lithium (24.00 mL. 38.40mmol) at -78° C. After stirring for 30 min, DMF (5.00 mL, 60.53 mmol)was added and the mixture was allowed to stir at room temperature for 2h. The reaction was quenched with water and extracted with ethyl acetate(3×150 mL). The combined organic extracts were dried (Na₂ SO₄) and thesolvent was removed under reduced pressure. Flash chromatography (1:1ether/hexane) of the residue afforded 5.42 g (76%) of the title compoundas a yellow solid: ¹ H NMR (250 MHz, CDCl₃) d 10.32 (s, 1H), 6.90 (s,1H), 6.82 (s, 1H), 4.57 (t, 2H), 3.91 (s, 3H), 3.25 (t, 2H).

f) Diethyl 2-(5-methoxy-2,3-dihydrobenzofuran-6-yliden)-malonate

To a solution of 5-Methoxy-2,3-dihydrobenzofuran-6-al (295 mg, 1.66mmol) in benzene was added diethyl malonate (265 mg, 1.66 mmol), aceticacid (20 mL, 0.35 mmol) and piperidine (30 mL, 0.30 mmol). The mixturewas heated at reflux for 3 h and then poured into 100 mL of water. Thismixture was extracted with three 50 mL portion of ethyl acetate. Thecombined organic extracts were washed with brine and dried (Na₂ SO₄).Removal of the solvent under reduced pressure gave quatitative yield ofthe title compound as a yellowish oil: ¹ H NMR (400 MHz, CDCl₃) d 8.02(s, 1H), 6.79 (s, 1H), 6.78 (s, 1H), 4.52 (t, 2H), 4.30 (m, 4H), 3.80(s, 3H), 3.18 (T, 2H), 1.28 (m, 6H).

g) Diethyl 2-(5-methoxy-2,3-dihydrobenzofuranyl)methyl-malonate

To a solution of diethyl2-(5-methoxy-2,3-dihydrobenzofuran-6-yliden)-malonate (1.80 g, 5.62mmol) in ethanol (25 mL) was added sodium borohydride (0.22 g, 5.66mmol) at room temperature. After stirring for 2 h the reaction wasquenched with water and extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were washed with brine and dried (Na₂ SO₄).After removing the solvent under reduced pressure, flash chromatography(1:1 diethyl ether/hexane) of the dark residue afforded 1.47 g (82%) ofthe title compound as a yellow oil: ¹ H NMR (250 MHz, CDCl₃) d 6.70 (s,1H), 6.54 (s, 1H), 4.44 (t, 2H), 4.12 (q, 2H), 3.74 (m, 4H), 3.11 (m,4H), 1.18 (t, 6H).

h) Ethyl, hydrogen2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl-malonate

To a solution of diethyl2-(5-methoxy-2,3-dihydrobenzofuranyl)methyl-malonate (6.55 g, 20.34mmol) in ethanol (50 mL) was added a solution of potassium hydroxide(1.35 g, 24.40 mmol) in water (10 mL). The reaction mixture was stirredat room temperature for 5 h. After concentrating the aqueous layer waswashed with ether and acidified with concentrated HCl to pH 1 andextracted with ethyl acetate (3×100 mL). The organic extracts werewashed with brine and dried (Na₂ SO₄). Removal of the solvent underreduced pressure gave 5.26 g (88%) of the title compound as a whitesolid: ¹ H NMR (250 MHz, CDCl₃) d 11.43 (b, 1H), 6.72 (s, 1H), 6.58 (s,1H), 4.48 (t, 2H), 4.16 (q, 2H), 3.82 (t, 1H), 3.75 (s, 3H), 3.14 (t,3H), 1.20 (t, 3H); MS (ESI) m/e 295.2 (M+H!⁺ ; m.p.: 114-116° C.

i) 4-Chloro-2-hydroxyacetophenone

In a 500 mL of round bottom flask purged with argon was placed 26.00 g(0.153 mol) of 3-acetoxychlorobenzene, cooled with ice bath. Then 30.00g (0.225 mol) of AlCl₃ was added in portions. The resulting mixture washeated to 140° C. for 2 h (caution: vigorous evolution of gas) and thencooled to 0° C., treated with 15 mL of conc. HCl in 100 mL of ice water.extracted with EtOAc (3×300 mL). The combined organic extracts werewashed with brine and dried (Na₂ SO₄). Removal of the solvent gave 24.00g (92%) of the title compound as a light yellow Liquid: ¹ H NMR (250MHz, CDCl₃) d 10.7 (s, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.98 (d, J=1.8 Hz,1H), 6.87 (dd, J=1.8, 8.6 Hz, 1H), 2.61 (s, 3H).

j) 4-Chloro-2-methoxymethoxyacetophenone

To a solution of 4-chloro-2-hydroxyacetophenone (22.00 g, 0.129 mol) inDMF (200 mL) was added K₂ CO₃ (72.00 g, 0.516 mol) and bromomethylmethylether (0.134 mol). After stirring at 55° C. for 1 h, the mixture waspoured into water and extracted with EtOAc (3×300 mL). The combinedorganic extracts were washed with brine and dried (Na₂ SO₄) and removalof the solvent under reduced pressure gave 25.00 g (90%) of the titlecompound as an oil: ¹ H NMR (250 MHz, CDCl₃) d 7.68 (d, J=8.3 Hz, 1H),7.22 (d, J=1.8 Hz, 1H), 7.00 (dd, J=1.8, 8.3 Hz, 1H), 5.28 (s, 2H), 3.53(s, 3H), 2.62 (s, 3H).

k) Methyl 2-(4-chloro-2-methoxymethoxy)benzoylacetate

To a solution of 4-Chloro-2-methoxymethoxyacetophenone (25.00 g, 0.116mol) in dimethyl carbonate (150 mL) was added 7.5 g of 80% NaH (0.257mol). After stirring for 10 min. at room temperature, the mixture washeated to 70° C. for 45 min. The resulting mixture was allowed to coolto room temperature and partitioned between water and ethyl acetate. Theorganic layer was separated and washed with brine and dried (Na₂ SO₄).Removal of the solvent under reduced pressure gave 29.00 g (92%) of thetitle compound as an oil: MS (ESI) m/z 273 (M+H)⁺ ; ¹ H NMR (400 MHz,CDCl₃) d 7.82 (d, J=8.4 Hz, 1H), 7.25 (d, J=1.8 Hz, 1H), 7.06 (dd,J=1.8, 8.4 Hz, 1H), 5.25 (s, 2H), 3.97 (s, 2H), 3.72 (s, 3H), 3.51 (s,3H).

I) Methyl(Z)-2-(4-chloro-2-methoxymethoxy)benzoyl-3-(dimethylamino)propenoate

A mixture of Methyl 2-(4-chloro-2-methoxymethoxy)benzoylacetate (24.00g, 0.107 mol) and N,N-dimethylformamide dimethyl acetal (25.51 g, 0.214mol) was heated to 90° C. overnight. Concentration under reducedpressure gave 34.86 g (100%) of the title compound as an oil: MS (ESI)m/z 328 (M+H)⁺ ; ¹ H NMR (400 MHz, CDCl₃) d 7.71 (s, 1H), 7.25 (d, 1H),7.13 (s, 1H), 7.00 (d, 1H), 5.12 (s, 2H), 3.46 (s, 6H), 3.44 (s, 6H).

m) Methyl 1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-ylcarboxylate

To a mixture of Methyl(Z)-2-(4-chloro-2-methoxymethoxy)benzoyl-3-(dimethylamino)propenoate(34.00 g, 0.104 mol) and n-butylhydrazine (37.00 g, 0.208 mol) in 600 mLof MeOH/H₂ O (9:1) was added NaOAc (84.86 g, 0.624 mol). The resultingmixture was stirred at room temperature overnight and then partitionedbetween water and CH₂ Cl₂. The organic layer was separated and washedwith brine and dried (Na₂ SO₄). Removal of the solvent under reducedpressure gave 35.50 g (97%) of the title compound as an oil: MS (ESI)m/z 353 (M+H)⁺ ; ¹ H NMR (400 MHz. CDCl₃) d 7.93 (s, 1H), 7.04-7.22 (m,3H), 5.01 (dd, J=6.8, 9.5 Hz, 2H), 3.75-3.92 (m, 2H), 3.60 (s, 3H), 3.30(s, 3H), 1.65 (m, 2H), 1.12 (m, 2H), 0.74 (t 3H.

n) 1-n-Butyl-5-(4-chloro-2-methoxymethoxyphenyl)4-hydroxymethylpyrazole

To a solution of Methyl1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-ylcarboxylate (10.00 g, 0.028 mol) in 200 mL of CH₂ Cl₂ at 0° C. was added85.2 mL of 1.5 M Dibal-H in toluene. After stirring for 1 h. thereaction was quenched with MeOH (100 mL) followed by addition of 35 mLof conc. HCl in 200 mL of water. The resulting mixture was stirred for15 min. and extracted with CH₂ Cl₂ (3×200 mL). The combined organicextracts were washed with brine and dried (Na₂ SO₄). Removal of thesolvent under reduced pressure gave 9.50 g (97%) of the title compoundas a oil: MS (ESI) m/z 325 (M+H)⁺ ; ¹ H NMR (400 MHz. CDCl₃) d 7.63 (s,1H), 7.13-7.29 (m, 3H), 5.09 (s, 2H), 4.36 (dd, 2H), 3.80-3.98 (m, 2H),3.35 (s, 3H), 1.70 (m, 2H), 1.18 (m, 2H), 0.81 (t, 3H).

o) 1-n-Butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-ylcarboxaldehyde

To a solution of1-n-Butyl-5-(4-chloro-2-methoxymethoxyphenyl)-4-hydroxymethylpyrazole(10.00 g, 30.86 mmol) in 150 mL of acetone at 0° C. was added of Jones'reagent until pink color persisted (30 mL), 60 mL of isopropyl alcoholwas then added and the resulting mixture was stirred at room temperaturefor 15 min, diluted with 300 mL of cold water, extracted with CH₂ Cl₂(3×200 mL). The combined organic extracts were washed with brine anddried (Na₂ SO₄). After removing the solvent under reduced pressure,flash column chromatography of the residue with 25% EtOAc in hexane gave5.50 g (56%) of the title compound as an oil: MS (ESI) m/z 323 (M+H)⁺ ;¹ H NMR (400 MHz, CDCl₃) d 9.54 (s, 1H), 8.07 (s, 1H), 7.35 (d, 1H),7.18 (m, 2H), 5.13 (s, 2H), 3.90-4.05 (m, 2H), 3.38 (s, 3H), 1.75 (m,2H), 1.20 (m, 2H), 0.83 (t, 3H).

p) Ethyl (E)-3-1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate

To a mixture of1-n-Butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-ylcarboxaldehyde (5.50 g, 17.08 mmol) and Ethyl, hydrogen2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl-malonate (7.28 g, 24.70mmol) in 50 mL of benzene was added piperidine (2.16 g, 25.41 mmol) andAcOH (0.51 g, 8.50 mmol), respectively. After heating at reflux for 3 h,the mixture was poured into water, extracted with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine and dried (Na₂ SO₄).After removing the solvent under reduced pressure, flash columnchromatography of the residue with 25% EtOAc in hexane gave 4.50 g (48%)of the title compound as an oil: MS (ESI) m/z 555 (M+H)⁺ ; ¹ H NMR (400MHz, CDCl₃) d 7.53 (s, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 7.13 (m, 2H),6.78 (s, 1H), 6.45 (s, 1H), 5.11 (s, 2H), 4.47 (t, 2H), 4.14 (m, 2H),3.89 (m, 2H), 3.85 (s, 3H), 3.38 (s, 3H), 3.16 (t, 2H), 1.65 (m, 2H),1.20 (t, 3H), 1.17 (m, 2H), 0.79 (t, 3H).

q) Ethyl (E)-3-1-n-butyl-5-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate

To a solution of Ethyl (E)-3-1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate (4.50 g, 8.10mmol) in EtOH (60 mL) was added 0.6 mL of conc. HCl. After heating atreflux for 3 h, the mixture was concentrated and then diluted withEtOAc. The resulting mixture was washed with 5% NaHCO₃, brine and dried(Na₂ SO₄). After removing the solvent, column chromatography of theresidue with 25% EtOAc in hexane gave 2.65 g (64%) of the title compoundas a solid: m.p. 158-160° C.; MS (ESI) m/z 511 (M+H)⁺ ; ¹ H NMR (400MHz, CDCl₃) d 7.58 (s, 1H), 7.47 (s, 1H), 7.02 (d, 1H), 6.78 (s, 1H),6.62 (dd, 1H), 6.59 (d, 1H), 6.48 (s, 2H), 5.50 (bs, 1H), 4.48 (t, 2H),4.12 (m, 2H), 3.85-3.95 (m, 4H), 3.83 (s, 3H), 3.81 (s, 3H), 3.16 (t,2H), 1.67 (m, 2H), 1.20 (t, 3H), 1.17 (m, 2H), 0.80 (t, 3H).

r) Methyl 3-chloro-2-methylbenzoate

To a solution of 3-chloro-2-methylbenzoic acid (1.00 g, 5.86 mmol) inmethanol (25 mL) was added 3 drops of sulfuric acid. The mixture wasstirred at reflux for 18 h. After concentrating the residue wasdissolved in ether, washed with 10% sodium hydroxide solution, brine anddried (Na₂ SO₄). Removal of the solvent under reduced pressure gave 0.95g (88%) of the title compound as a white solid: ¹ H NMR (250 MHz, CDCl₃)d 7.62 (d, 1H), 7.41 (d, 1H), 7.05 (t, 1H), 3.82 (s, 3H), 2.55 (s, 3H).

s) 2-Chloro-6-methyl carboxylate benzylbromide

To a solution of methyl 3-chloro-2-methylbenzoate (1.30 g, 7.04 mmol) inbenzene (20 mL) was added NBS (1.50 g, 8.45 mmol) and benzoyl peroxide(0.20 g, 0.83 mmol). After stirring at reflux for 18 h, the mixture waspoured into water, and the resulting mixture was extracted with ethylacetate (3×50 mL). The combined organic extracts were washed with brineand dried (Na₂ SO₄). After removing the solvent under reduced pressure,flash column chromatography (1:1 ether/hexane) of the residue gave 1.87g (82%) of the title compound as a dark oil: ¹ H NMR (250 MHz, CDCl₃) d7.72 (d, 1H), 7.55 (d, 1H), 7.21 (t, 1H), 5.09 (s, 2H), 3.92 (s, 3H.

t) Ethyl (E)- 1-n-butyl-5-2-(2-methoxycarbonyl)phenylmethoxy-4-chloro-phenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate

To a solution of the ethyl (E)-1-n-butyl-5-(2-hydroxy-4-chlorophenyl)-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate (0.20 g, 0.39mmol) and methyl 2-bromomethyl-3-chlorobenzoate (0.13 g, 0.47 mmol) inDMF (5 mL) was added sodium hydride (0.02 g, 0.59 mmol) at 0° C. Themixture was stirred at room temperature for 4 h. After an aqueous workup, extracting with ethyl acetate (3×15 mL), the combined organicextracts were washed with brine and dried (Na₂ SO₄). After removing thesolvent under reduced pressure, flash column chromatography (1:1 ethylacetate/hexane) of the residue afforded the title compound as an oil(0.22 g, 80%). ¹ H NMR (250 MHz, CDCl₃) d 7.78 (d, 1H), 7.55 (d, 1H),7.48 (s, 1H), 7.32 (m, 2H), 7.12 (d, 2H), 6.75 (s, 1H), 6.45 (s, 1H),5.55 (dd, J=10, 27.5 Hz, 2H), 4.49 (t, 2H), 4.10 (q, 2H), 3.83 (s, 3H)3.77 (t, 2H), 3.65 (s, 3H), 3.15 (t, 2H), 1.52 (quintet, 2H), 1.20 (t,3H), 1.05 (sextet, 2H), 0.75 (t, 3H).

u) (E)-3- 1-n-Butyl-5-2-(2-carboxy-6-chlorophenyl)methoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-propen-2-oic acid

To a solution of the ethyl (E)- 1-n-butyl-5- 2-2-(methoxycarbonyl)-6-chlorophenylmethoxy!-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate (0.20 g, 0.29mmol) in methanol (5 mL) was added a solution of sodium hydroxide (0.04g, 0.87 mmol) in water (2 mL). The mixture was stirred at reflux for 18h. The methanol was removed under reduced pressure and the aqueous layerwas washed with ether. The aqueous layer was then acidified withconcentrated HCl to pH 1 and extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were washed with water, brine and dried (Na₂SO₄). Removal of the solvent gave a solid. Recrystallization frommethanol yielded the title compound as a light yellow solid (0.17 g,91%): ¹ H NMR (400 MHz CDCl₃) d 7.75 (d, 1H), 7.80 (s, 1H), 7.48 (m,2H), 7.33 (s, 1H), 7.25 (t, 1H), 7.10 (s, 1H), 7.05 (m, 2H), 6.65 (s,1H), 6.35 (s, 1H), 5.49 (dd, J=10, 27.5 Hz, 2H), 4.40 (t, 2H), 3.79 (m,5H) 3.63 (t, 2H), 3.05 (t, 2H), 1.50 (quintet, 1H), 1.30 (quintet, 1H),0.94 (quintet, 2H), 0.60 (t, 3H); MS(ESI) m/e 652.2 M+H!⁺ ; mp: 155-157°C. (methanol); Anal. (C₃₄ H₃₂ Cl₂ N₂ O₇) calcd: C, 62.62; H, 4.96; N,4.30. found: C, 62.40; H, 5.32; N, 4.19.

EXAMPLE 2 (E)-3- 1-n-Butyl-5-2-(2-carboxyphenyl)methoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid

a) Ethyl (E)-3- 1-n-Butyl-5-2-(2-methoxycarbonyl)phenylmethoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate

Following the procedure of Example (1t) except substituting methyl2-bromomethylbenzoate for methyl 2-bromomethyl-3-chlorobenzoate, thetitle compound was prepared in 85% yield.

b) Following the procedure of Example (1u) except substituting Ethyl(E)-3- 1-n-Butyl-5-2-(2-methoxycarbonyl)phenylmethoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate for ethyl(E)- 1-n-butyl-5- 2-2-(methoxycarbonyl)-6-chlorophenylmethoxy!-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-2-propenoate, the titlecompound was prepared in 90% yield as a white solid: R_(f) 0.58 (1:1EtOAc/hexane with 1% AcOH); ¹ H NMR (400 MHz CDCl₃) d 8.19 (d, 1H), 7.58(s, 1H), 7.53 (s, 1H), 7.49 (t, 1H), 7.30 (m, 2H), 7.13 (m, 3H), 6.77(s, 1H), 6.48 (s, 1H), 5.52 (bs, 2H), 4.45 (t, 2H), 3.92 (m, 2H) 3.82(s, 3H), 3.80 (bs, 2H), 3.12 (t, 2H), 1.65 (m, 2H), 1.12 (m, 2H), 0.76(t, 3H); MS(ESI) m/e 618 M+H!⁺ ; mp: 116-118° C. Anal. (C₃₄ H₃₃ ClN₂O₇.0.5H₂ O) calcd: C, 65.22; H, 5.47; N, 4.47. found: C, 65.03; H, 5.33;N, 4.37.

EXAMPLE 3 (E)-3- 1-n-Butyl-5-2-(2-carboxyphenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(dihydrobenzofuran-5-yl)methyl!-prop-2-enoic acid 98-99° C. EXAMPLE 4(E)-3- 1-n-Butyl-5-2-(2-Carboxyphenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(6-methoxy-2,3-dihydrobenzofuran-5-yl)methyl!-prop-2-enoic acid 104-106°C. EXAMPLE 5 (E)-3- 1-n-Butyl-5-2-(2-Carboxyphenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid 198-200°C. EXAMPLE 6 (E)-3- 1-n-Butyl-5-2-(2-Carboxy-6-chlorophenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid EXAMPLE7 (E)-3- 1-n-Butyl-5-2-(2-Carboxy-5-chlorophenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid 122-124°C. EXAMPLE 8 (E)-3- 1-n-Butyl-5-2-(2-Carboxy-4-chlorophenyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid 120-122°C. EXAMPLE 9 (E)-3- 1-n-Butyl-5-2-(3-carboxy-2-pyridyl)methoxy-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-5-yl)methyl!-prop-2-enoic acid EXAMPLE10 (E)-3- 1-n-Butyl-5-2-(cyclopentyloxy)-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid 156-158°C. EXAMPLE 11 (E)-3- 1-n-Butyl-5-2-(N,N-diethylamido)methoxy-4-methoxyphenyl)-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid 178-180°C. EXAMPLE 12 (E)-3- 1-n-Butyl-5-2-(5-tetrazolyl)methoxy!-4-methoxyphenyl-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)-methyl!-prop-2-enoicacid 128-130° C. EXAMPLE 13 (E)-3- 1-n-Butyl-5-2-(2-picolyl)oxy-4-methoxy!phenyl-1H-pyrazolyl-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)-methyl!-prop-2-enoicacid 132-135° C. EXAMPLE 14 (E)-3- 1-n-Butyl-5-2-(2-Carboxy-5-chlorophenyl)methoxy-4-chlorophenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid 110-112°C. EXAMPLE 15 (E)-3- 1-n-Butyl-5-2-(4-methoxyphenoxy)-4-methoxyphenyl!-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl!-prop-2-enoic acid 91-92°C. EXAMPLE 16 (E)-3- 1-n-Butyl-5-2-N-ethyl-5-tetrazolyl)methoxy!-4-methoxyphenyl-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrofuran-6-yl)methyl!-prop-2-enoic acid EXAMPLE 17(E)-3- 1-n-Butyl-5-1-N-ethyl-5-tetrazolyl)methoxy!-4-methoxyphenyl-1H-pyrazol-4-yl!-2-(5-methoxy-2,3-dihydrofuran-6-yl)methyl!-prop-2-enoic acid EXAMPLE 18

Formulations for pharmaceutical use incorporating compounds of thepresent invention can be prepared in various forms and with numerousexcipients. Examples of such formulations are given below.

Inhalant Formulation

A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metereddose inhaler to deliver the desired amount of drug per use.

    ______________________________________    Tablets/Ingredients   Per Tablet    ______________________________________    1. Active ingredient  40 mg    (Cpd of Form. I)    2. Corn Starch        20 mg    3. Alginic acid       20 mg    4. Sodium Alginate    20 mg    5. Mg stearate        1.3 mg                          2.3 mg    ______________________________________

Procedure for tablets:

Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitablemixer/blender.

Step 2 Add sufficient water portion-wise to the blend from Step 1 withcareful mixing after each addition. Such additions of water and mixinguntil the mass is of a consistency to permit its conversion to wetgranules.

Step 3 The wet mass is converted to granules by passing it through anoscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4 The wet granules are then dried in an oven at 140° F. (60° C.)until dry.

Step 5 The dry granules are lubricated with ingredient No. 5.

Step 6 The lubricated granules are compressed on a suitable tabletpress.

Parenteral Formulation

A pharmaceutical composition for parenteral administration is preparedby dissolving an appropriate amount of a compound of formula I inpolyethylene glycol with heating. This solution is then diluted withwater for injections Ph Eur. (to 100 ml). The solution is then steriledby filtration through a 0.22 micron membrane filter and sealed insterile containers.

We claim:
 1. A compound of Formula (I): ##STR48## wherein (Z) is##STR49## P is tetrazol-5-yl,! CO₂ R₆ or C(O)N(R₆)S(O)_(q) R₁₀ ;R^(a) isindependently hydrogen or C₁₋₆ alkyl; R₁ is independently hydrogen, Ar,C₁₋₆ alkyl or C₁₋₆ alkoxy; R₂ is ##STR50## R₃ and R₅ are independentlyR₁₃ OH, C₁₋₈ alkoxy, S(O)_(q) R₁₁, N(R₆)₂, NO₂, Br, F, I, Cl, CF₃,NHCOR₆, R₁₃ CO₂ R₇, --X--R₉ --Y, --X(C(R₆) ₂)OR₆, --(CH₂) _(m) X'R₈ or--X(CH₂)_(n) R₈ wherein each methylene group within --X(CH₂) _(n) R₈ maybe unsubstituted or substituted by one or two --(CH₂)_(n) Ar groups; R₄is independently R₁₁, OH, C₁₋₅ alkoxy, S(O)_(q) R₁₁, N(R₆)₂, Br, F, I,Cl or NHCOR₆, wherein the C₁₋₅ alkoxy may be unsubstituted orsubstituted by OH, methoxy or halogen; R₆ is independently hydrogen orC₁₋₈ alkyl; R₇ is independently hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl orC₂₋₈ alkynyl, all of which may be unsubstituted or substituted by one ormore OH, N(R₆)₂, CO₂ R₁₂, halogen or XC₁₋₁₀ alkyl; or R₇ is (CH₂)_(n)Ar; R₈ is independently R₁₁, CO₂ R₇, CO₂ C(R₁₁)₂ O(CO)XR₇, PO₃ (R₇)₂,SO₂ NR₇ R₁₁, NR₇ SO₂ R₁₁, CONR₇ SO₂ R₁₁, SO₃ R₇, SO₂ R₇, P(O)(OR₇)R₇,CN, CO₂ (CH₂)_(m) C(O)N(R₆)₂, C(R₁₁)₂ N(R₇)₂, C(O)N(R₆)₂, NR₇ C(O)NR₇SO₂ R₁₁, OR₆, or tetrazole which is substituted or unsubstituted by C₁₋₆alkyl; R₉ is independently a bond, C₁₋₁₀ alkylene, C₁₋₁₀ alkenylene,C₁₋₁₀ alkylidene, C₁₋₁₀ alkynylene, all of which may be linear orbranched, or phenylene, all of which may be unsubstituted or substitutedby one of more OH, N(R₆)₂, COOH or halogen; R₁₀ is independently C₁₋₁₀alkyl, N(R₆)₂ or Ar; R₁₁ is independently hydrogen, Ar, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, all of which may be substituted or unsubstitutedby one or more OH, CH₂ OH, N(R₆)₂, or halogen; R₁₂ is independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₇ alkynyl; R₁₃ is independentlydivalent Ar, C₁₋₁₀ alkylene, C₁₋₁₀ alkylidene, C₂₋₁₀ alkenylene, all ofwhich may be unsubstituted or substituted by one or more OH, CH₂ OH,N(R₆)₂ or halogen; R₁₄ is independently hydrogen, C₁₋₁₀ alkyl, XC₁₋₁₀alkyl, Ar or XAr; R₁₅ is independently hydrogen, Ar, C₁₋₆ alkyl, or XAr;R₁₆ is independently C₁₋₆ alkyl or phenyl substituted by one or moreC₁₋₆ alkyl, OH, C₁₋₅ alkoxy, S(O)_(q) R₆, N(R₆)₂, Br, F, I, Cl, CF₃ orNHCOR₆ ; X is independently (CH₂)_(n), O, NR₆ or S(O)_(q) ; X' isindependently O, NR₆ or S(O)_(q) ; Y is independently CH₃ or X(CH₂)_(n)Ar; Ar is; ##STR51## naphthyl; all of which may be unsubstituted orsubstituted by one or more Z₁ or Z₂ groups;A is independently C═O , or(C(R₆)₂)_(m) ; B is independently --CH₂ -- or --O--; Z₁ and Z₂ areindependently hydrogen, XR₆, C₁₋₈ alkyl, (CH₂)_(q) CO₂ R₆, C(O)N(R₆)₂,CN, (CH₂)_(n) OH, NO₂, F, Cl, Br, I, N(R₆)₂, NHC(O)R₆, O(CH₂)_(m)C(O)NR_(a) SO₂ R₁₆, (CH₂)_(m) OC(O)NR_(a) SO₂ R₁₆, O(CH₂)_(m) NR_(a)C(O)NR_(a) SO₂ R₁₆ tetrazolyl which may be substituted or unsubstitutedby C₁₋₆ alkyl, CF₃ or C(O)R₆ ; m is independently 1 to 3; n isindependently 0 to 6; q is independently 0, 1 or 2; provided R₃, R₄ andR₅ are not O--O(CH₂)_(n) Ar or O--OR₆ ; or a pharmaceutically acceptablesalt thereof.
 2. A compound of Formula (I) of claim 1 wherein P is CO₂R₆ ; R₁ is hydrogen; R₃ and R₅ are independently hydrogen, CO₂ R₆, OH,C₁₋₈ alkoxy, C₁₋₈ alkyl, N(R₆)₂, NO₂, Br, F, Cl, I, R₁₃ CO₂ R₇,X(CH₂)_(n) R₈, (CH₂)mX'R₈, or X(C(R₆)₂)_(m) OR₆ ; R₄ is hydrogen, OH,C₁₋₅ alkoxy, N(R₆)₂, Br, F, Cl, I, NHCOCH₃, or S(O)_(q) C₁₋₅ alkylwherein the C₁₋₅ alkyl may be unsubstituted or substituted by OH,methoxy or halogen; R₆ is hydrogen, methyl or ethyl; R₇ is hydrogen,C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl, all of which may beunsubstituted or substituted by one or more OH, N(R₆)₂, CO₂ R₁₂,halogen, or R₇ is (CH₂)_(n) Ar wherein n is zero or 1 and Ar issubstituted phenyl; R₁₁ is hydrogen, phenyl, all of which may besubstituted or unsubstituted by one or two C₁₋₄ alkyl groups; C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, all of which may be substituted orunsubstituted by one or more OH, CH₂ OH, N(R₆)₂, or halogen; R₁₂ ishydrogen or C₁₋₆ alkyl; R₁₃ is phenyl, or C₂₋₁₀ alkylene, all of whichmay be unsubstituted or substituted by one or more CO₂ R₆, OH, CH₂ OH,N(R₆)₂, or halogen; and R₁₅ is hydrogen or C₁₋₆ alkyl.
 3. A compound ofclaim 2 wherein P is CO₂ H; R₁ is hydrogen; Z₁ and Z₂ are independentlyhydrogen, CO₂ R₆, (CH₂)_(n) OH, C₁₋₄ alkyl or C₁₋₆ alkoxy; R₃ is Br, Cl,C₁₋₈ alkoxy or X(CH₂)_(n) R₈, wherein X is O, n is 0, 1, or 2, and R₈ isselected from; CO₂ H, OH, tetrazolyl optionally substituted by C₁₋₈alkyl; CONR₇ SO₂ R₁₁ wherein R₇ is H or C₁₋₈ alkyl, R₁₁ is C₁₋₈ alkyl orphenyl optionally substituted by Br, Cl, F, C₁₋₈ alkyl; or R₈ is phenylsubstituted by one or more Br, Cl, CO₂ H, CH₂ OH; R₅ is methoxy orN(R₆)₂ wherein R₆ is H or methyl; R₄ is hydrogen; R₆ is hydrogen, methylor ethyl; R₇ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₈ alkynyl,all of which may be unsubstituted or substituted by one or more OH,N(R₆)₂, CO₂ R₁₂, halogen, or R₇ is (CH₂)_(n) Ar wherein R₇ is (CH₂)_(n)Ar and n is preferably zero or 1 and Ar is preferably phenyl substitutedor unsubstituted by halogen or C₁₋₅ alkoxy; R₁₁ is hydrogen, phenyl, allof which may be substituted or unsubstituted by one or two C₁₋₄ alkylgroups; C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, all of which may besubstituted or unsubstituted by one or more OH, CH₂ OH, N(R₆)₂, orhalogen; R₁₂ is hydrogen or C₁₋₆ alkyl; R₁₃ is phenyl or C₂₋₁₀ alkylene,all of which may be unsubstituted or substituted by one or more CO₂ R₆,OH, CH₂ OH, N(R₆)₂, or halogen; and R₁₅ is hydrogen, ethyl, isopropyl,n-butyl, cyclopropylmethyl or cyclopropylethyl.
 4. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 5. A method of treatment of diseases caused by anexcess of endothelin comprising administering to a subject in needthereof, an effective amount of an endothelin receptor antagonist ofclaim
 1. 6. A method of treating hypertension, renal failure orcerebrovascular disease which comprises administering to a subject inneed thereof, an effective amount of a compound of claim
 1. 7. A methodfor the treatment of chronic renal failure which comprises administeringto a subject in need thereof, an effective amount of a compound ofclaim
 1. 8. A method of treatment of benign prostatic hypertrophy whichcomprises administering to a subject in need thereof, an effectiveamount of a compound of claim
 1. 9. A method of treatment of congestiveheart failure which comprises administering to a subject in needthereof, an effective amount of a compound of claim
 1. 10. A method oftreatment of unstable angina, coronary vasospasm and myocardial salvage,which comprises administering to a subject in need thereof, an effectiveamount of a compound of claim
 1. 11. A method of preventing or treatingrestenosis which comprises administering to a subject in need thereof,an effective amount of a compound of claim
 1. 12. A method of treatmentof pulmonary hypertension which comprises administering to a subject inneed thereof, an effective amount of a compound of claim
 1. 13. A methodof treatment of atherosclerosis which comprises administering to asubject in need thereof, an effective amount of a compound of claim 1.14. A method of preventing and treating the sequelae of diabetes whichcomprises administering to a subject in need thereof, an effectiveamount of a compound of claim
 1. 15. A method of treatment of stroke orsubarachnoid hemorrhage which comprises administering to a subject inneed thereof, an effective amount of a compound of claim 1.